Early descriptions of the disease used the terms fibromuscular hyperplasia or fibroplasia, but now the term fibromuscular dysplasia (FMD) is used. McCormack et al in 1958 reported a pathological description of fibromuscular hyperplasia in four patients with renovascular hypertension 1. In 1965, Hunt et al 2 observed that the disease was heterogeneous and not necessarily associated with hyperplasia, and introduced the term FMD. It was soon recognized that FMD could be present in carotid arteries without documented renal artery FMD or hypertension 3. FMD is currently defined as an idiopathic, segmental, non-inflammatory and non-atherosclerotic disease of the musculature of arterial walls, leading to stenosis of small and medium-sized arteries. FMD may be familial (OMIM #135580).

A pathological classification of renal artery FMD was proposed by McCormack et al 45 and revised by Stanley 6. It was based on the dominant arterial wall layer involved: the intima, media or adventitia. Three main types of FMD have been identified: intimal, medial and perimedial 6, and these types have also been described in extrarenal arteries 7. Intimal FMD, which accounts for 5% or renal artery FMD cases, is characterized by irregularly arranged mesenchymal cells within a loose matrix of subendothelial connective tissue and a fragmented internal elastic lamina. Nearly 85% of all FMD stenoses in the renal arteries are medial FMD; the lesion is a homogeneous collar of elastic tissue that presents as multiple stenoses interspersed with aneurismal outpouchings, with a preserved internal elastic lamina. Perimedial FMD affects approximately 10% of dysplastic renal arteries and involves excessive tissue deposition at the junction of the media and adventitia. The three types are not mutually exclusive. Indeed, Stanley reported that medial and perimedial FMD lesions can coexist in the same arterial segment 6; and Alimi et al analyzed arterial segments from 33 patients and found that more than one artery layer was involved in 25 (66%) of the 38 specimens studied 8.

Since reports of successful outcomes of angioplasty in patients with renal artery FMD 9, surgery has been used only rarely for patients with FMD and consequently histological verification is available for only a small minority of cases. As a result, contemporary reports infer the pathological type of FMD from the angiographic appearance of arterial lesions. Table 1 shows the distribution of pathological types and the angiographic appearance of FMD in two series in which both pathological and angiographic findings were reported 34.

Most commonly affected are the renal and carotid arteries. Involvement of the axillary, iliac, basilar, hepatic and intracranial arteries has also been reported. In a comprehensive review of the literature, Mettinger and Ericson analyzed reports concerning a total of 1197 patients with FMD 11. Renal arteries were involved in 58% of cases, cervicocranial arteries in 32%, and other arteries in 10%. The type of FMD and any coexistence of FMD in several arterial beds were not reported. In a series of 104 patients with renal artery FMD documented at angiography 12, 81 (78%) had the string-of-bead sign; FMD affected both renal arteries in 54 patients. Among the 81 patients in whom the carotid arteries were examined, 9 (11%) had carotid artery FMD. In a series of 37 patients with carotid artery FMD 13, 23 (62%) had the "string-of-beads" feature; half the patients were hypertensive, but none underwent renal artery angiography.

Unlike atherosclerotic stenoses, stenoses due to FMD rarely affect the ostial or proximal segments of arteries. FMD stenoses of renal arteries are usually truncal or distal and may involve arterial branches 34567; they are more frequent on the right side 37. Most of carotid artery FMD lesions occur adjacent to the C1–2 interspace 1314.

Macroaneurysms affecting the renal or carotid arteries are more frequent in FMD than in the general population (see Epidemiology section below). As intracranial aneurysms may rupture and lead to subarachnoid or intracerebral hemorrhage, the American Heart Association recommends performing magnetic resonance angiography of the head in patients with cervical artery FMD 15. Spontaneous cervical artery dissections are a common cause of stroke in young and middle-aged adults and are associated with FMD in about 15% of cases 16. Spontaneous renal artery dissections are rare but frequently coexist with FMD 1718. Aneurysms and dissections are considered to be complications of FMD but frequently arise in individuals with no FMD. Therefore, their presence without direct evidence of FMD does not suffice to diagnose the condition 6.

The prevalence of FMD is not precisely known. Ten to 20% of documented renal artery stenoses are the consequence of FMD, and renovascular hypertension is documented in less than 1 to 2% of hypertensive patients. Assuming a 20% prevalence of hypertension in middle-aged subjects, the prevalence of clinically significant renal artery FMD can be estimated to be about 0.4%. The prevalence of asymptomatic renal artery FMD is, however, one order of magnitude higher: four reports of angiographic findings for a total of 3181 potential kidney donors describe 139 subjects (4.4%) with evidence of FMD 19202122. The reports did not provide details concerning the radiological criteria used to define the condition, however. The number of reported cases of carotid artery FMD is about half that of renal artery FMD (see above) 11.

Renal artery aneurysms were identified in four of 716 (0.6%) potential kidney donors in one series, all four having lesions suggestive of FMD 21; similarly 12 of the 125 (9.6%) patients with renal artery FMD reported by Kincaid et al had renal artery aneurysms 3. The prevalence of intracranial aneurysms in the general population is estimated to be 1 to 5% 23 but was 7.3% in a meta-analysis combining data from 18 reports describing patients with carotid artery FMD 24. The prevalence of carotid artery dissection in the general population is about 1 per 100,000. To our knowledge, there are no reliable estimates of the prevalence of renal artery dissection in the general population or of the prevalence of dissection in patients with cervical or renal artery FMD.

Medial-type FMD and/or FMD showing the "string-of-beads" appearance at angiography are usually diagnosed in young adults and are more than four times as frequent in women as in men. A male predominance in found in cases with intimal-type FMD or with focal stenoses at angiography, but these cases make up only a minority of patients with FMD 12 (Figure 3).

The most common clinical presentation of FMD is renovascular hypertension secondary to renal artery involvement. Renal artery stenosis due to FMD may be associated with all stages of hypertension, but it is most commonly detected in patients with stage 2–3 hypertension, or abrupt onset or resistant hypertension, since these are the individuals who undergo the most comprehensive etiological examinations. Upper abdominal quadrant or flank bruits are common in patients with renal artery FMD 612 but this clue has only limited diagnostic sensitivity and specificity 25. FMD may be complicated by renal artery dissection and kidney infarction with abrupt flank pain, hematuria and rapidly progressive hypertension 18. As a result of activation of the renin-angiotensin system, hypokalemia reflecting secondary hyperaldosteronism may be present, particularly in cases complicated with renal artery dissection and kidney infarction 1826. Unlike atherosclerotic renal artery stenosis, FMD renal artery disease is rarely associated with high serum creatinine levels.

Cervical artery FMD, mainly affecting the internal carotid artery, is seldom symptomatic. It can be discovered incidentally by Doppler ultrasound during evaluation of dizziness, headache, or an asymptomatic cervical bruit 11. Neurological symptoms occur when FMD lesions are complicated by brain ischemia, embolus, and thrombosis in cases with dissection or associated aneurysms rupture. Complications may present as Horner's syndrome, transient ischemic attack, ischemic stroke or subarachnoid hemorrhage. The association in a given patient of hemorrhage due to aneurysm rupture and ischemic stroke due to stenosis is characteristic of cerebral FMD 13.

FMD affecting extra-renal and extra-cervical arteries has been reported in celiac, superior and inferior mesenteric, hepatic, splenic, and coronary arteries 7. Although most patients with digestive artery FMD are asymptomatic, they can present with mesenteric ischemia (postprandial abdominal pain, weight loss and epigastric bruit), or rarely mesenteric infarction and multi-organ failure 27. Patients with lower limb artery FMD may present with cold legs, intermittent claudication, or evidence of distal embolic disease. Patients with subclavian artery FMD may present with arm weakness, paresthesias, claudication, and subclavian steal syndrome 713.

More patients with FMD than matched controls smoke 72829 and FMD patients who smoke have a more severe arterial disease than those who do not 30. The mechanisms by which smoking contributes to the etiology of FMD have, however, not been elucidated. The well-documented majority of women among patients with FMD (Figure 3) suggests that exposure to endogenous or exogenous estrogens may predispose to the condition, but the number of pregnancies and the frequency of oral contraceptive use does not differ between patients with FMD and matched controls 729. Renal mobility when assuming the upright position is greater in women than in men and in the right than in the left kidney 29: FMD is more frequent in women than in men and in the right than in the left kidney, so it has been suggested that repeated stretching of the renal artery may cause micro traumas that predispose to FMD 7. However Sang et al found that kidney mobility during maximal respiratory cycle or during a change in posture did not differ between patients with FMD and matched controls with normal renal arteries 29.

The occurrence of renal FMD in sib pairs or identical twins 31 suggests its possible inheritability. The first formal pedigree analysis was performed by Rushton 32 who suggested that FMD is transmitted as an autosomal dominant disease with incomplete penetrance and variable clinical symptoms. However, his conclusions were drawn from interviews of relatives who were considered to have FMD but whose arterial disease also included peripheral arterial occlusion or coronary heart disease, i.e. conditions more likely to be associated with atherosclerosis than with FMD. Our retrospective analysis of 104 patients with renal FMD showed a prevalence of 11% for familial cases, i.e. 11% of cases had at least one sibling with angiographic evidence of renal artery FMD 12. However, familial detection based on angiography is not practicable in relatives who are normotensive or asymptomatic. As renal artery FMD may be associated with only mild hypertension or even present in normotensive subjects (see data concerning kidney donors above), the presence of FMD is probably overlooked in many relatives of index cases. High-resolution echo-tracking methods are promising alternatives to angiography for screening asymptomatic relatives because subclinical alterations of the common carotid artery wall seem common in patients with renal artery, medial FMD 33. Using this technique, elevated echo-tracking scores of the carotid artery have been found in first-degree relatives of index cases and the findings are consistent with the possibility of autosomal dominant transmission 34.

Few molecular genetic studies have been conducted, because of the absence of large affected pedigrees and/or the absence of large and well-phenotyped cohorts allowing powerful case-control studies. Autoimmunity has been implicated by a limited study showing an association with HLA Drw6 29 but this has not been confirmed. In a larger series involving 161 patients and 3 sets of controls, we did not find any association with functional polymorphisms of the α-1 antitrypsin gene 35. Bofinger et al reported an association with polymorphisms of the renin angiotensin system 36 but this finding also has not been confirmed.

The presence of renal artery FMD can be documented by the following non-invasive tests (in increasing order of accuracy): the captopril test, captopril renal scintigraphy, Doppler ultrasound, magnetic resonance angiography, gadolinium-enhanced magnetic resonance angiography, and computed tomographic angiography 37. Doppler ultrasound is a time-consuming, examiner-dependent procedure and has several limitations including obesity, poor compliance for respiratory renal movement, and failure to visualize entire arteries or to define accessory arteries. Computed tomographic angiography is the most specific test in patients at risk of harboring FMD renal artery stenosis (Figure 4), but gadolinium-enhanced magnetic resonance angiography has the advantages of no radiation exposure and limited nephrotoxicity. A careful prospective multicenter comparative study found that computed tomographic angiography and gadolinium-enhanced magnetic resonance angiography had reasonably good specificities for detecting renal artery stenosis due to FMD (92 and 84 percent, respectively) but disappointing sensitivities (64 and 62 percent, respectively) 38.

There is no published comparative study of non-invasive tests for detecting carotid artery FMD, although Doppler ultrasound may disclose irregular patterns of stenosis that are suggestive. Computed tomographic angiography and magnetic resonance angiography are probably more effective than ultrasonography for detecting lesions of the middle and distal portions of the carotid and vertebral arteries and may also document or rule out the association of intracranial aneurysms.

The commonly accepted gold standard for diagnosing renal artery FMD is intra-arterial angiogram with digital subtraction. This invasive test should be reserved for patients in whom it is clinically justified to proceed with revascularization in the same procedure. Stenosis quantification is, however, frequently difficult in medial FMD with the "string-of-beads" appearance because multiple web-like defects are often present in patients with FMD, contributing to clinically significant stenoses that may not be apparent on angiography.

The value of treatment has not been established for renal artery FMD without hypertension. The management of hypertension associated with renal artery FMD involves revascularization and/or antihypertensive medication. There have been no controlled trials comparing revascularization to medication in FMD. Current recommendations reflect the knowledge acquired concerning atherosclerotic renovascular hypertension, although indications for balloon angioplasty are wider in FMD than in atherosclerotic renovascular disease because the blood pressure outcome of angioplasty is more favorable in FMD than in atherosclerosis 9. Revascularization is recommended for patients with hemodynamically significant renal artery stenosis – i.e. with bilateral stenoses or a unilateral stenosis causing more than 60% reduction in luminal diameter – and accelerated hypertension, resistant hypertension, malignant hypertension, hypertension with an unexplained unilateral small kidney, and hypertension with intolerance to medication 15. It is also useful in young patients with recent-onset hypertension and hemodynamically significant renal artery stenosis due to FMD: in these cases the goal is to cure the hypertension. The standard revascularization procedure is balloon angioplasty with bailout stent placement if necessary. Surgical reconstruction is indicated for patients with complex FMD that extends to segmental arteries and those with macroaneurysms 15. Antihypertensive drug treatment is indicated for patients with long-standing hypertension or in cases with persistent hypertension following revascularization. Medication includes angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers and betablockers. In cases with hemodynamically significant stenosis and no indication for primary revascularization, renal echography should be performed every year and revascularization considered if kidney length shortens by 1 cm or more.

Management of dissecting carotid artery FMD includes anticoagulation and, in cases with expanding or symptomatic pseudoanevrysm, percutaneous angioplasty or surgical repair 43. Therapeutic options for securing ruptured intracerebral aneurysms are microvascular neurosurgical clipping and endovascular coiling 44.